The precise cellular and molecular mechanisms by which metabolic syndromes increase the risk of dementia remain to be elusive. We recently demonstrate that eNOS-haploinsufficient mice spontaneously develop marked age-dependent changes of cerebral amyloid angiopathy, astrogliosis/microgliosis, microbleeds/BBB disruption, and severely impaired spatial working memory. They thus represent a unique and ideal model for studying mechanistic link between metabolic changes and dementia. We speculate that blood-born factors, especially metabolic inflammatory factors, can be pathogenic from poor metabolic conditions to the brain via small secretory vesicles named exosomes. Our long-term goal is to identify such factors. Herein, we found that miRNA 21 (miR-21) is possibly one of these factors that is markedly upregulated in the exosomes isolated from the blood plasma of middle-aged eNOS-deficient mice and later in the brain. In situ hybridization indicates striking colocalization of miR-21 with neuron (NeuN), activated microglia (Iba1) and oligodendrocytes (NG2), most prominently in the forebrain including the frontal cortex and hippocampus. Our preliminary data also suggests that peripherally derived miRNAs can impact brain functions via exosomes trafficking through BBB under systemic inflammatory conditions. We therefore hypothesize that 1) elevated miR-21 in eNOS mice plays essential roles in the pathogenesis of this aging and neurodegenerative model. Therefore, eliminating miR-21 elevation systemically will prevent neurodegeneration. 2) Peripherally elevated miR-21 encapsulated in circulating exosomes contributes to the neuronal dysfunction, neuroinflammation and neurodegeneration in eNOS model. The elevated circulating miR-21 may be used as a diagnostic marker for aging and dementia. Accordingly, three specific aims are proposed to test the hypotheses in eNOS model that 1) elevated miR-21 plays a causative role in neurodegenerative phenotypes; 2) peripheral circulating miR-21 contributes to CNS dysfunctions and neurodegeneration; and 3) elevated miR-21 can be used as a biomarker predicting dementia in patients with vascular syndrome. Pharmacological, genetic (brain cell-type specific knock-out), systems biology, as well as conventional behavioral, biochemical and histological analysis will be utilized. Positive outcomes from this study will provide proof-of-concept that peripheral cell-derived vesicles under metabolic/inflammatory conditions contribute to neuroinflammation and impair cognitive functions. This may not only advance our knowledge of the pathogenesis of cognitive impairments, but also help the development of diagnostics and biomarkers.